More than 12 million Americans have tried methamphetamine (METH), and 1.5 million use the drug regularly. METH is known to cause partial dopamine depletion in the caudate/putamen (striatum) in humans, and these depletions cause long-term deficits in the cognitive functions of METH abusers. This grant will therefore focus on examining the molecular and cellular processes underlying the impact of METH-induced neurotoxicity to striatum dopamine systems on learning and memory processes so that such insight can be applied to improving behavioral and pharmacological management of individuals with a history of METH abuse and addiction. This study will first examine altered brain circuitry in a learning task that is mediated by the striatum. It will be determined through examination of gene expression in various brain areas which brain regions besides the striatum are involved in this kind of task in rats that have been pretreated with a neurotoxic regimen of METH. Successful completion of this study will increase understanding of cognition in METH addicts and potentially improve cognitive rehabilitation of METH abusers who have quit using the drug, because rehabilitation can be focused on those brain regions most affected by METH. In the second part of this grant, the impact of L-DOPA on striatal learning and memory in METH-pretreated rats will be examined. L- DOPA is a drug commonly used to treat Parkinson's disease, and does so by increasing the amount of dopamine in the brain. This proposal will test whether a systemic injection of L-DOPA can increase dopamine transmission in the striatum by three methods: measuring dopamine content in neurons in the striatum, measuring dopamine neurotransmitter release in the striatum from electrically stimulated neurons, and examining gene expression in rats performing a striatally-mediated behavioral task. These methods will determine at molecular, physiological, and behavioral levels whether L-DOPA can improve cognitive function after a partial dopamine loss induced by METH. PUBLIC HEALTH RELEVANCE: Abuse of methamphetamine is a detrimental problem to society, and leads to long- lasting cognitive deficits in the caudate and putamen. This proposal will examine how cognition is altered as a result of methamphetamine toxicity, and whether proper brain functioning can be restored by use of the drug commonly employed for treatment of Parkinson's disease, L-DOPA.